Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms — rigidity, bradykinesia and tremor — due to loss of ...dopaminergic neurons. The motor symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others. In recent years, many studies have investigated the progression of the hallmark symptoms over time, and the cardinal motor symptoms have different rates of progression, with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor. The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability. Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms. However, the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability. Further, none of the currently-available therapies can slow or halt the disease progression. Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression. In this article, the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.
Lactate has long been considered an intermediate by-product of glucose metabolism. However, in recent years, accumulating evidence reveals that lactate has unique biological activities. In previous ...studies, lactate signaling was shown to inhibit inflammation. Furthermore,
experiments have shown that lactate can promote the transformation of pro-inflammatory macrophages into anti-inflammatory macrophages. However, no
studies have shown whether lactate can alleviate inflammation.
RAW 264.7 macrophages were stimulated by LPS to induce an M1 phenotype, and cultured with low and high concentrations of lactate. The cells were then observed for phenotypic transformations and expression of inflammatory mediators and surface markers. The expression of inflammatory factors was also analyzed in the cell-free supernatant fraction. Further, a mouse model of DSS-induced colitis was established and treated with lactate. Colonic tissue injury was monitored by histopathological examinations.
The
experiments showed that lactate promoted the transformation of activated macrophages to M2 phenotype and decreased the expression of TLR4-mediated NF-κB signaling proteins and inflammatory factors. In the DSS-induced colitis mouse model, lactate promoted the phenotypic transformation of macrophages in colonic tissue, reduced inflammation and organ damage, inhibited the activation of TLR4/NF-κB signaling pathway, decreased the serum levels of pro-inflammatory factors, increased the expression of anti-inflammatory factors, promoted the repair of the intestinal mucosal barrier and reduced the severity of colitis.
Lactate inhibits the TLR/NF-κB signaling pathway and the production of pro-inflammatory factors by promoting polarization of macrophages. In addition, lactate promotesthe repair of the intestinal mucosal barrier and protects intestinal tissue in inflammation. Furthermore, lactate is relatively safe. Therefore, lactate is a promising and effective drug for treating inflammation through immunometabolism regulation.
We studied the functions of sodium tanshinone IIA sulfonate (TSA) in inducing tumor growth in obstructive sleep apnea (OSA)-mimicking intermittent hypoxia (IH) xenograft mice and the underlying ...potential molecular mechanism.
RNA sequencing was conducted to screen the differentially expressed microRNAs in cell lines exposed to IH with or without TSA treatment. As part of the 5-week
study, we treated xenograft mice with 8-h IH once daily. TSA and miR-138 inhibitors or mimics were administrated appropriately. In addition, we performed real-time quantitative polymerase chain reaction (RT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), microvessel density (MVD), and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays.
RNA sequencing and RT-PCR results demonstrated that TSA increased the levels of miR-138 under IH conditions
. TSA reduced the IH-stimulated high levels of hypoxia-induced factor-1α and vascular endothelial growth factor. Furthermore, IH contributed to high tumor migration, invasion, MVD, and low apoptosis. TSA attenuated IH-mediated tumor proliferation, migration, invasion, MVD, and increased apoptosis, whereas miR-138 inhibitor interrupted the effect of TSA on treating IH-induced tumor behaviors.
OSA mimicking IH facilitates tumor growth and reduces miR-138 levels. TSA inhibits IH-induced tumor growth by upregulating the expression of miR-138.
Purpose
The authors consider the mutual benefits of the ceding company and reinsurance company in the design of reinsurance contracts. Two objective functions to maximize social expected utilities ...are established, which are to maximize the sum of the expected utilities of both the ceding company and reinsurance company, and to maximize their products. The first objective function, additive, emphasizes the total gains of both parties, while the second, multiplicative, accounts for the degree of substitution of gains of one party through the loss of the other party. The optimal price and retention of reinsurance are found by a grid search method, and numerical analysis is conducted. The results indicate that the optimal solutions for two objective functions are quite different. However, optimal solutions are sensitive to the change of the means and volatilities of the claim loss for both objective functions. The results are potentially valuable to insurance regulators and government entities acting as reinsurers of last resort.
Design/methodology/approach
In this paper, the authors apply relatively simple, but in the view significant, methods and models to discuss the optimization of excess loss reinsurance strategy. The authors only consider the influence of loss distribution on optimal retention and reinsurance price but neglect the investment factor. The authors also consider the benefits of both ceding company and reinsurance company to determine optimal premium and retention of reinsurance jointly based on maximizing social utility: the sum (or the product) of expected utilities of reinsurance company and ceding company. The authors solve for optimal solutions numerically, applying simulation.
Findings
This paper establishes two optimization models of excess-of-loss reinsurance contract against catastrophic losses to determine optimal premium and retention. One model considers the sum of the expected utilities of a ceding company and a reinsurance company's expected utility; another considers the product of them. With an example, the authors find the optimal solutions of premium and retention of excess loss reinsurance. Finally, the authors carry out the sensitivity analysis. The results show that increasing the means and the volatilities of claim loss will increase the optimal retention and premium. For objective function I, increasing the coefficients of risk aversion of or reducing the coefficients of risk aversion of will make the optimal retention reduced but the optimal premium increased, and vice versa. However, for objective function 2, the change of coefficient of risk aversion has no effect on optimal solutions.
Research limitations/implications
Utility of the two partners: The ceding company and the reinsurance company, may have different weights and different significance. The authors have not studied their relative significance. The simulation approach in numerical methods limits us to the probability distributions and stochastic processes the authors use, based on, generally speaking, lognormal models of rates of return. This may need to be generalized to other returns, including possible models of shocks through jump processes.
Practical implications
In the recent two decades, reinsurance companies have played a great role in hedging mega-catastrophic losses. For example, reinsurance companies (and special loss sharing arrangements) paid as much as two-thirds of the insured losses for the September 11, 2001 tragedy. Furthermore, large catastrophic events have increased the role of governments and regulators as reinsurers of last resort. The authors hope that the authors provide guidance for possible balancing of the needs of two counterparties to reinsurance contracts.
Social implications
Nearly all governments around the world are engaged in regulation of insurance and reinsurance, and some are reinsurers themselves. The authors provide guidance for them in these activities.
Originality/value
The authors believe this paper to be a completely new and original contribution in the area, by providing models for balancing the utility to the ceding insurance company and the reinsurance company.
研究目的
我們探討分出公司和再保險公司在再保險合約的設計上、如何能達至互利互惠。研究確立了兩個目標函數，分別為把分出公司和再保險公司兩者之預期效用的總和最大化，以及把它們的產品最佳化。第一個目標函數是加法的，強調兩個參與方的總增益;而第二個目標函數則是乘法的，這個目標函數，闡釋參與方因另一方虧損而有所收益之取代度。再保險的最佳價格和自留額是利用網格搜索法找出的，數值分析也予以進行。研究結果顯示，兩個目標函數的最佳解決方案甚為不同。唯最佳解決方案會對就這兩個目標函數而言的追討損失的波動、以及其平均值之改變產生敏感反應。研究結果將會見其價值於作為在萬不得已的時候的再保險人的保險業規管機構和政府實體。
研究設計/方法/理念
在這學術論文裡，我們採用了相對簡單、但我們認為是重要的方法和模型，來探討超額賠款再保險策略的優化課題。我們只考慮虧損分佈對最佳自留額和再保險價格的影響，而不去檢視投資因素。我們亦考慮對分出公司和再保險公司兩者的利益，來釐定最佳保費和再保險的自留額，而這兩者則共同建基於把社會效益最大化之上：再保險公司和分出公司的預期效益的總和 (或其積數) 。 我們採用類比模仿方法、來解決尋求在數字上最佳解決方案的問題。
研究結果
本研究建立了就應對嚴重虧損而設的兩個超額賠款再保險合約的優化模型，來釐定最佳的保費和自留額。其中一個模型考慮了分出公司和再保險公司兩者各自的預期效益的總和。另外的一個模型則考慮了兩者的預期效益的積數。透過例子，我們找到了保費和超額虧損再保險自留額的最佳解決方案。最後，我們進行了敏感度分析。研究結果顯示、若增加追討損失的平均值和波動，則最佳自留額和保費也會隨之而增加。就第一個目標函數而言，若增加風險規避係數、或減少這個係數，則最佳自留額會隨之而減少，但最佳保費卻會隨之而增加，反之亦然。唯就第二個目標函數而言，風險規避係數的改變，對最佳解決方案是沒有影響的。
研究的局限/啟示
– 有關的兩個夥伴之效用性：分出公司和再保險公司或有不同的份量和重要性。我們沒有探討兩者的相對重要性。
– 我們以數值方法為核心的類比模仿研究法、使我們局限於機率分配和一般而言建基於投資報酬率對數常態模型之隨機過程的使用。我們或許需要調節研究法。以能概括其它回報收益，包括透過跳躍過程而可能達至之沖擊模型。
實務方面的啟示
在過去20年裡，再保險公司在控制極嚴重災難性的損失上曾扮演重要的角色。例如、再保險公司 (以及特殊的損失分擔安排) 為了2001年9月11日的災難事件而支付多至保險損失的三分之二的費用。而且，重大的災難性事件使政府及作為最後出路再保險人的調控者得扮演更重要的角色。我們希望研究結果能為再保險合約兩對手提供指導，以平衡雙方的需要。
社會方面的啟示
全球差不多每個政府都參與保險和再保險的管理工作，有部份更加本身就是再保險人。研究結果為他們的管理工作提供了指導。
研究的原創性/價值
我們相信本學術論文、提供了平衡分出保險公司和再保險公司效用性的模型，就此而言，本論文在相關的領域上作出了全新和獨創性的貢獻。
Purpose
Epidemiologic findings are inconsistent regarding the association between attention‐deficit/hyperactivity disorder (ADHD) medication exposure and suicide attempt in individuals with ADHD.
...Methods
A systematic literature search of PubMed, Embase and Cochrane Library up to February 2020 was performed. A meta‐analysis was conducted for outcomes in which a summary risk ratio (RR) was calculated when taking heterogeneity into account.
Results
Both population‐level and within‐individual analyzes showed that ADHD medication was associated with lower odds of suicide attempts (RR = 0.76, 95% confidence interval CI, 0.58‐1.00; P = .049 and RR = 0.69; 95% CI, 0.49‐0.97; P = .049, respectively). However, the association only existed for participants who were treated with stimulants (RR = 0.72; 95% CI, 0.53‐0.99; P = .042 on population‐level analysis and RR = 0.75; 95% CI, 0.66‐0.84; P < .001 on within‐individual analysis). Furthermore, a lower risk of suicide attempts was not observed in subjects who took ADHD medication for 1 to 90 days (RR = 0.91; 95% CI, 0.74‐1.13; P = .416 on within‐individual analysis).
Conclusion
The results indicate that non‐stimulant treatment is not associated with a higher risk of suicide attempt, but stimulant treatment is associated with a lower risk of suicide attempt.
•24 novel monoterpenoid indole alkaloid (MIA)-like analogs were designed and prepared by biomimetic synthetic strategy.•Compound 17 displayed approximately 47-fold stronger diphenolase inhibitory ...activity than that of loganetin.•Molecular docking study indicated that compound 17 might exert inhibitory activity by binding to the key amino acid residues (His 85 and His 263) at the tyrosinase active site.
A series of novel monoterpenoid indole alkaloid (MIA)-like analogs (1–24) were synthesized by using a biomimetic synthetic strategy and combinatorial chemistry. The tyrosinase inhibitory activities and antioxidant properties of these compounds were assessed through tyrosinase inhibition assay, DPPH and ABTS free radicals scavenging assays, respectively. The results showed that most synthesized compounds (2, 4–8, 10–12, 14–17, 19) exhibited significant inhibitory activities against both monophenolase and diphenolase. In particular, compound 14, with an IC50 value of 0.18 ± 0.02 mM, displayed approximately 72-fold stronger monophenolase inhibitory activity than that of loganetin with an IC50 value of 12.76 ± 1.00 mM. Similarly, compound 17 exhibited the best diphenolase inhibitory activity (IC50, 0.30 ± 0.09 mM), which was approximately 47 times higher than that of loganetin (IC50, 14.05 ± 0.47 mM). Additionally, six compounds (3, 13–17) showed significant in vitro antioxidant activities. Compound 17 exhibited the most promising ABTS radical scavenging activity with an IC50 value of 2.90 ± 0.07 μM, while compound 15 exhibited the highest DPPH free radical scavenging capacity with an IC50 value of 17.59 ± 0.21 μM. The structure-activity relationships analysis revealed that the substituents at C-5 and C-11 in the tryptamine moiety might significantly impact antioxidant activity. Furthermore, the detailed interactions and binding modes of the most potent derivative toward tyrosinase were elucidated by a molecular docking study, which indicated that 14 and 17 might exert their inhibitory effects by binding to key amino acid residues (His 85 and His 263) at the tyrosinase active site.
A carbene insertion into electron‐deficient C−H bonds of 1,3‐diesters, β‐ketoesters, β‐ketonitriles, and malononitriles was realized by using CuCN/PCy3 as the catalyst. The reaction provides a ...straightforward approach to the synthetically important multi‐substituted succinic acid derivatives. A plausible reaction mechanism with cyclopropanation/ring opening as key steps was proposed based on control experiments.
Copper catalysis: A formal carbene insertion into electron‐deficient C−H bonds of 1,3‐diesters, β‐ketoesters, β‐ketonitriles, and malononitriles was realized by using CuCN/PCy3 as the catalyst. The reaction provides a straightforward approach to the multi‐substituted succinic acid derivatives. The mechanistic studies suggested that this formal C−H bond insertion reaction likely proceeds through a cyclopropanation of enol and a ring‐opening reaction sequence.
Graphene, a single atomic layer of sp2-hybridized carbon atoms arranged in a hexagonal structure and the Nobel winning material in 2010, has attracted extensive research attention in the last few ...years due to its outstanding physical, chemical, electrical, optical and mechanical properties. To further extend its potential applications, intensive research efforts have been devoted to the functionalization of graphene. Examples include improving graphene solubility by attaching different chemical functional groups to its basal plane, modulating the charge carrier type and concentration via surface transfer doping by coating it with various metals films or organic molecules, improving the bio-selectivity by decorating it with different π-conjugated organic molecules, and so on. Different methods have been developed to functionalize graphene. Among them, non-covalent molecular functionalization represents one of the most effective and promising methods. The extended π-conjugation is largely preserved without creating extensive structural defects on the graphene sheet, thereby retaining the high charge carrier mobility. In this review, a brief summary about different functionalization methods of graphene and its derivatives by covalent and non-covalent interactions will be presented, with particular focus on the non-covalent molecular functionalization. A broad review of the applications of non-covalently functionalized graphene and its derivatives will be presented in detail, including field-effect-transistors, organic optoelectronics, and molecular sensing.
Smart microimplants are playing increasing roles in modern medicine. Wireless power transfer (WPT) and data communication are essential components in microimplants. In order to minimize device size, ...a preferred design is to share the wireless power channel with the data communication links consisting of a downlink and an uplink. While the implementation of the downlink is relatively easy, the uplink from the implant to the external unit is difficult to implement due to the limited power supply and small transceiver coil available within the implant. In this work, we present a new design of the data uplink that utilizes a special tapped coil and a simple passive circuit to produce a strong pulsed magnetic field (PMF) for signal emission. The strong PMF, which is oscillatory at the same resonant frequency as the WPT carrier, allows wireless data transmission over a longer distance through the WPT channel. Our new design is studied analytically, and the function of our circuit is confirmed by a computer simulation. A prototype is constructed, and its performance is compared with the existing load shift keying (LSK) method. Our experimental result showed that the design produced more than 15 times stronger signal strength at the receiving end.
This research analyzes the area required for the conflict resolution between aircraft in two flows impacted by a convective weather cell (CWC). The CWC is introduced as a constrained area, forbidden ...to flight through, which affects the air traffic flows. Prior the conflict resolution, two flows and their intersection are relocated away from the CWC area (thus enabling circumvention of the CWC), which is followed by a tuning of the relocated flows intersection angle in order to create the minimal size of the conflict zone (CZ—a circular area centered at the intersection of two flows, which provides aircraft enough space to completely resolve the conflict within). Therefore, the essence of the proposed solution is in providing conflict free trajectories for the aircraft in intersecting flows that are affected by the CWC, with the goal of minimizing the CZ size, so the finite occupied airspace for the conflict resolution and the CWC circumvention could be reduced. Compared to the best solutions and current industry practice, this article is focused in reduction of the airspace required for aircraft to aircraft and aircraft to weather conflict resolution, and not to distance travelled, time savings, and fuel consumption minimization. The conducted analysis in the MicrosoftExcel2010 confirmed the relevance of the proposed model and demonstrated variations in efficiency of the utilized airspace. The proposed model's transdisciplinary nature makes it potentially applicable in other fields of study, such as the conflict resolution between unmanned aerial vehicles (UAVs) and fixed objects like buildings. Building on this model and taking in consideration large and complex data sets, such as weather related data and flight data (aircraft position, speed, and altitude), we believe it is possible to conduct more sophisticated analyses that would take advantage of Big Data.
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